Microneedles are a recent invention arising from the application of etching and lithographic techniques from the semiconductor fabrication processes, to produce sharp, high aspect ratio, solid or hollow features on materials such as plastics or metals, which are termed “microneedles” because they have dimensions on the micrometer scale.
Microneedles have strong potential for the transdermal delivery of a very wide range of drugs, pharmacologically active agents and therapeutic agents, for both immediate effect and possibly for sustained action through appropriate formulation enhancements, and indeed have found potential applications as a mechanism for the delivery of drugs and various therapeutic molecules. The range of molecules in terms of size, chemistry or the dosage formulation in which the agent is contained that may be administered into humans and animals using microneedles is virtually unlimited.
There are a number of advantages associated with the use of microneedles for the delivery of drugs through the skin, i.e. transdermally. The first of these relates to the advantages relating to the mechanism of drug absorption and distribution when administered through the skin, such as avoidance of the first pass metabolism by the liver, and a reduction of side effects, together with the rapid onset of action. Additionally in this case there are a number of further advantages ranging from the ability to deliver drugs of almost any physicochemical nature, any type of formulation, e.g., liquid, gel, emulsion, or even as a solid whereby the drug could form part of the needle or be used to coat the needle.
Microneedles are generally fabricated in arrays, synthesised using etching techniques, such as chemical or physical etching and standard lithographic procedures. The materials used range from silicon to polymers such as PDMS. They generally measure tens of microns to hundreds of microns in length and have varying tip diameters, usually less than 10 microns.
Some examples of microneedles are shown in FIG. 16.
It has been demonstrated (“Microfabricated microneedles: a novel approach to transdermal drug delivery” J Pharm Sci. 1998 August; 87(8):922-5”) that application of microneedles on the human skin for 10 seconds resulted in a 1000-fold increase in permeability of the skin to calcein. However upon removal of the microneedle array there was a 10,000-fold increase in permeation. i.e., drug was able to permeate much more readily through the holes/microchannels created by the microneedles.
It has also been demonstrated (“Transdermal delivery of desmopressin using a coated microneedle array patch system”. J Control Release. 2004 Jul. 7; 97(3):503-11) that an array of solid microneedles coated with the drug desmopressin was able to deliver more than 90% of the drug transdermally, with metabolites comparable to those produced when desmopressin is delivered intravenously.
The delivery of vaccines requires a strong immune response to optimise the effect of the drug, and such response is generally achieved through the use of adjuvants designed to boost the immune response. The skin is a major immunological organ with antigen-presenting Langerhans cells in rich supply, covering almost 15% of the surface area of the skin. Vaccines delivered by the transdermal route are taken up by these Langerhans cells and migrate to the lymph nodes where antigen-specific immunity is activated. This provides a highly efficient means therefore for administering vaccines.
Skin Penetration
The mechanics of microneedle insertion into the skin are critical to its practical application. Needles with the correct geometry and physical properties, such as strength, are able to penetrate the skin provided the penetration force is less than the breaking force of the needle/tip. The optimum needle types are those with a small tip radius and high wall thickness.
Another factor for drug delivery is ensuring that microneedles penetrate to the correct depth. Penetration depth is partly dictated by needle shape, and partly by needle diameter, inter-needle spacing, length and applied force.
In addition to the design and geometry of the needles due consideration must be given to the method by which the microneedles are applied to the skin, to ensure the requisite depth of penetration occurs, and such that drug permeation is predictable and not erratic.
There are a number of organizations developing microneedle based systems for the drug delivery applications, and each is developing and optimising the needles for its particular application. Generally speaking these systems are split between using solid microneedles to simply create cavities through which drug will then permeate, and using hollow microneedles, the bore of which acts as a conduit for the transport of drug from a reservoir upon compression of the drug reservoir, usually by hand.
The mechanism by which microneedles are adhered or applied to the skin is therefore very important and a number of different techniques are illustrated in the literature. The most common method is depression of an array of microneedles on the skin and holding for a defined period of time. For example, it is known from International Patent Application WO 2006/055771 to propel a microneedle array to the skin surface from a predetermined distance, whereas International Patent Application WO 2006/055795 teaches that a flexible sheet can be used to move a microneedle array in the direction of the skin surface.
An alternative propulsion means is known from International Patent Application WO 2006/055802, which uses an elastic band to propel a microneedle array towards the skin. Finally, International Patent Application WO 2007/002521 teaches an impactor which accelerates a microneedle array towards the surface of the skin, moving along an arcuate path.
Another known device is the ‘Dermaroller™’, which is used for both cosmetic and drug delivery applications. This uses a cylinder with surface projections of solid stainless steel microneedles of varying geometries. Cavities are created in the skin using the solid array of microneedles. Drug delivery is achieved by using the roller to ‘press’ drug or cosmetic material stored on a needle-free area of the roller in to the cavities created. An example of the roller is shown in FIG. 17.
A number of mechanisms have been developed to address the need for a reproducible means of applying the microneedles to the skin, which is crucial to their clinical exploitation. The majority of methods rely on the impact of an array of needles with the skin, either through mechanical means or manually by depressing with the thumbs for example.
The Dermaroller is one example whereby the force is applied using a cylinder to simultaneously bring the needles into contact with the skin and apply pressure over the region where the needles are in contact with the skin, followed by a region where the outer surface of the cylinder is absent of needles and is coated with drug which are claimed to be manually compressed and forced into the cavities created by the microneedles. There are two problems with the Dermaroller. First, the surface area of the skin through which drug permeation will occur cannot be easily determined as there is no mechanism for limiting the area over which the Dermaroller is applied. Secondly, the technique is inherently unreliable in accurately delivering a defined quantity because it depends entirely upon drug entering the skin through a combination of diffusion and forced entry by compression through the cavities created by the needles. In a clinical setting it is very important to be able to accurately define how much drug is administered.
The other known microneedle devices do not provide a satisfactory means of supplying accurate quantities of drugs transdermally in a controllable fashion, nor any means for staged delivery.
Embodiments of the invention overcome the problems with the Dermaroller and improve on the known devices.